. 2021 Oct 21;28(1):25–50. doi: 10.1097/MCC.0000000000000902

Table 3.

Clinical trials of CPAP in acute hypoxemic respiratory failure of COVID-19 etiology

Publication	PMID	Study design	Setting	Patient Population	Treatment	Intubation Rate	Mortality Rate	Main finding	Secondary findings
Aliberti et al.[81], 2020	32747395	Observational prospective multicenter cohort study	High dependency unit	COVID-19 AHRF PaO₂/FiO₂ 142 [97–203] 65 patients with limitations of treatment 92 patients with no limitations of treatment	Helmet CPAP n = 157 PEEP 10.8 (2.3) cmH₂O 4 cases discontinued CPAP for intolerance	Overall population, CPAP failure 45% [37 to 52] Patients with no limitations of treatment, CPAP failure 37% [95% CI 28 to 47]	Overall cohort 29% [95% CI 22 to 36] Patients with limitations of treatment 55% [95% CI 43 to 67] Patients with no limitations of treatment 10% [95% CI 5 to 18]	Helmet CPAP is feasible in the high dependency unit and is associated with a failure rate < 40% in patients with no limitations of treatment with moderate to severe AHRF.	CPAP failure was associated with the severity of pneumonia on admission and higher baseline values of interleukin-6.
Alviset et al.[82], 2020	33052968	Retrospective study	Mixed setting	COVID-19 AHRF SpO2 < 90% oxygen therapy 15lt/min with nonrebreather face mask	Face Mask CPAP n = 41 PEEP 5–10 cmH₂O 2 cases discontinued CPAP for intolerance	59% [95% CI 43 to 72]	29% [18 to 44]	CPAP is feasible outside of the ICU	The intubation rate was lower than 60%, with a mortality rate less than 1/3.
Arina et al.[79], 2020	33196858	Retrospective study	ICU	COVID-19 AHRF PaO₂/FiO₂ 97 [75–135]	CPAP n = 93 CPAP settings are not provided The exact number of patients with limitations of treatment is not provided	Failure in the overall cohort was 66% [55 to 74] 47 (51%) of patients were intubated, while 14 (15%) had CPAP as ceiling of treatment	43% [33 to 53]	At a multivariate model C-reactive protein and NT-proBMP had sensitivity of 0.75 [95% CI 0.62 to 0.86] and specificity of 0.83 [95% 0.61–0.95].	After 6 h of treatment in patients of the CPAP success group a PaO₂/FiO₂ raise of 77% was observed, while a raise of only 38% in patients that failed CPAP.
Bellani et al.[69^▪], 2021	33395553	Single day observational study	Ward	COVID-19 AHRF PaO₂/FiO₂ 172 (102)	NIV + CPAP n = 798 215 (27%) patients with limitations of treatment Helmet was used for 617 patients, face mask for 248 Noninvasive respiratory support initiated 1 [0–4] days after hospital admission PEEP was 10.8 (2.6), ranging from 2 to 20	Noninvasive respiratory support failure 38% [95% CI 34 to 41] in the overall cohort Noninvasive respiratory support failure 27% [23 to 30] in patients with no limitations of treatment cohort Noninvasive respiratory support failure 67% [61 to 73] in patients with limitations of treatment cohort	Overall mortality was 25% [95% CI 22 to 28]	Noninvasive respiratory support outside the ICU is feasible and approximately 10% of COVID-19 patients present in the hospital were treated with noninvasive respiratory support, with a predominant use of helmet CPAP.	Overall rate of success was > 60% in the overall cohort and 73% in patients with no limitations of treatment.
Brusasco et al.[89], 2021	33033151	Retrospective multicenter study	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 119 [99–153]	CPAP n = 64 PEEP 10 cmH₂O in all patients	CPAP failure 17% [10 to 28] ETI 11% [5 to 21]	Overall mortality 14% [95% CI 8 to 25] Died on CPAP 6% [95% CI 2 to 15] Died on IMV 8% [95% CI 4 to 17]	CPAP was feasible in patients with moderate to severe AHRF	At univariate analysis CPAP failure correlated with sex, hypertension, diabetes, COPD, three or more comorbidities and lung weight, but at multivariate analysis only hypertension remained significant (OR 7.33, 95% CI 1.5 to 34, P = 0.012).
Burns et al.[78], 2020	32624494	Retrospective study	Non-ICU	COVID-19 AHRF SpO2 < 94% in Venturi Mask 40%	CPAP n = 23 BIPAP n = 5 BIPAP settings: max PEEP = 10.2 (2.9) cmH₂O max Pinsp = 22.4 (6) cmH₂O CPAP settings: Max PEEP = 12.7 (2.1) cmH₂O	Not reported	BIPAP 40% [95% CI 12 to 77] CPAP 52% [33 to 71]	Ward based noninvasive respiratory support is a good treatment option, with a mortality around 50%.	The only statistically significant difference between survivors and nonsurvivors was the presence of ‘classical’ imaging appearances, P = 0.034.
Carteaux et al.[81], 2021	33655452	Retrospective study	Intermediate Care Unit and ICU	COVID-19 AHRF PaO₂/FiO₂ 160 [115–258]	CPAP n = 85 Interface: oro-nasal mask CPAP was designed with a Boussignac valve protected by a filter, and free flow oxygen rate of 15 l/min [15–15]	Predefined criteria for intubation were present. 64% [95% CI 53 to 73]	27% [95% CI 19 to 37]	Adding a filter to the Boussignac valve does not affect the delivered pressure but may variably increase the resistive load depending on the filter used.	Clinical assessment suggests that CPAP designed with a Boussignac valve and a filter is a frugal solution to provide a ventilatory support and improve oxygenation during a massive COVID-19 outbreak.
Coppadoro et al.[77], 2021	33627169	Retrospective multicenter study	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 103 [79–176]	CPAP n = 306 Patients with no limitations of treatment n = 176 Patients with limitations of treatment n = 130 PEEP 10 [7–10] cmH₂O Helmet CPAP was delivered for 21 h/day, for the first 48 h, and from day 3 to 5 for 19 h/day	CPAP failure overall cohort 48% [95% CI 42 to 54] CPAP failure in patients with no limitations of treatment 31% [24 to 38]	Hospital mortality in patients with no limitations of treatment 12% [95% CI 8 to 18] Hospital mortality in patients with limitations of treatment 72% [95% CI 64 to 79]	Treatment of COVID-19 AHRF outside the ICU is feasible with Helmet CPAP, with a mortality rate of 12%. It was also used in patients with limitations of treatment, improving survival in almost 1/3 of cases.	CPAP failure was independently associated with C-reactive protein, time to oxygen mask failure, lower PaO₂/FiO₂ during CPAP and number of comorbidities.
Corradi et al.[77], 2020	33197604	Single-center pilot study	ICU	COVID-19 AHRF PaO₂/FiO₂ 195 [168–246]	Helmet CPAP n = 27 PEEP = 10 cmH₂O	Predefined criteria for ETI 33% [95% CI 17 to 52]	11% [95% CI 4 to 28]	CPAP failure was significantly associated with diaphragmatic thickening fraction at multivariate analysis, the best threshold was 21.4%
De vita et al.[80], 2021	33500220	Retrospective multicenter study	High Intensity Unit	COVID-19 AHRF PaO₂/FiO₂ success 120 [75–160] PaO₂/FiO₂ failure 103 [60–152]	CPAP n = 367 Helmet was applied in 281 (77%) patients and face mask in 71 (19%) patients. Values from 15 patients were missing. Initial PEEP was 10–12 cmH₂O, to be increased up to 15cmH₂O	Predefined criteria for intubation 41% [95% CI 36 to 46]	Not reported	In patients treated with CPAP, age, LDH and percentage change in PaO₂/FiO₂ after starting are predictors of intubation.	The use of CPAP avoided IMV in more than half of the patients.
Duca et al.[60], 2020	32766538	Retrospective study	Non-ICU	COVID-19 AHRF CPAP PaO₂/FiO₂ 131 [97–190] NIV PaO₂/FiO₂ 87 [53–120] IMV at arrival PaO₂/FiO₂ 76 [60–177]	CPAP n = 71 Helmet CPAP, PEEP = 15 [12–18] cmH₂O NIV n = 7 NIV, PEEP = 16 [12–20] cmH₂O IMV at arrival = 7 IMV at arrival, PEEP = 18 [10–18] cmH₂O	CPAP intubation rate 37% [95% CI 26 to 48] NIV intubation rate 0% [95% CI 0 to 35] CPAP failure 92% [95% CI 83 to 96] NIV failure 57% [95% CI 25 to 84]	CPAP 76% [95% CI 65 to 84] NIV 57% [95% CI 25 to 84] IMV at arrival 100% [95% CI 65 to 100]	In case of limited resources, the use of early CPAP or NIV in the ward or in the emergency department could be a valid strategy.	CPAP failure occurred in a high percentage of patients.
Faraone et al.[61], 2020	33222116	Retrospective study	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 130 (65) 25 (50%) patients had patients with limitations of treatment	NIV n = 25 CPAP n = 25 Interface: full face or oro-nasal mask Duration of treatment in the overall cohort: 187 (181) hours PEEP started at 5 cmH₂O, up to 12 cmH₂O IPAP set at 15cmH₂O, up to 20–25 cmH₂O	Patients with no limitations of treatment: 36% [95% CI 20 to 55] CPAP failure 44% [95% CI 27 to 63] NIV failure 68% [95% CI 48 to 83]	Patients with limitations of treatment 88% [95% CI 70 to 96] Patients with no limitations of treatment 12% [95% CI 4 to 30]	Noninvasive respiratory was useful in avoiding intubation in patients with no limitations of treatment.	The rate of infection among healthcare workers was low.
Franco et al.[67^▪▪], 2020	32747398	Retrospective multicenter study	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 138 (66)	HFNO n = 163 CPAP n = 330 PEEP 10.2 (1.6) cmH₂O Helmet 149 (99%) Face mask 2 (1%) NIV n = 177 PEEP 9.5 (2.2) cmH₂O Pressure Support 17.3 (3) cmH₂O Helmet 15 (21%) Face mask 57 (79%)	Recieved IMV: HFNO 29% [95% CI 24 to 36] CPAP 25% [95% CI 20 to 30] NIV 28% [95% CI 22 to 35] HFNO Failure 38% [Ci 31 to 47] CPAP Failure 47% [95% CI 42 to 53] NIV Failure 53% [95% CI 46 to 60]	30 day mortality: HFNO 16% [95% CI 11 to 22] CPAP 30% [95% CI 26 to 35] NIV 31% [95% CI 24 to 38] Difference not significant at adjusted analysis	Noninvasive respiratory support outside of ICU is feasibile, and mortality rates compare favourably with previous reports. There was no difference among the interfaces at the adjusted analysis.	Noninvasive respiratory support was associated with risk of staff contamination.
Gaulton et al.[87], 2020	32984836	Retrospective, multicenter study	ICU	COVID-19 AHRF SpO₂ < 92% with 6l/min nasal cannula Body mass index, kg/m2, mean (sd) = 35.5 (8.6)	Helmet CPAP n = 17 HFNO n = 42 PEEP 5–10 cmH₂O	ETI at 7 days CPAP 18% [6 to 41] HFNO 52% [38 to 67]	Death at 7 days CPAP 6% [1 to 27] HFNO 19% [10 to 33]	Difference in the intubation rate was significant after adjustment for age.	In obese patients Helmet CPAP is effective in reducing the ETI rate.
Kofod et al.[84], 2021	33889343	Retrospective study	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 101 (36) Patients with no limitations of treatment n = 27 Patients with limitations of treatment n = 26	CPAP n = 53 Interface: Face Mask 30 patients received CPAP between 18 and 24 h a day. PEEP 10.5 [10–12] cmH₂O	CPAP failure overall cohort 72% [49 to 87] CPAP patients with no limitations of treatment 25% [95% CI 15 to 38]	Overall mortality 58% [45 to 71] CPAP limitations of treatment 92% [95% CI 76 to 98] CPAP patients with no limitations of treatment 13% [7 to 25]	CPAP seems to have positive effect on oxygenation and respiratory rate in most patients with severe respiratory failure caused by COVID-19, but the prognosis for especially elderly patients with high oxygen requirement and with a ceiling of treatment in the ward is poor.	A positive and significant (P = 0.002) immediate response of CPAP was seen on respiratory rate, decreased from 28.6 (7.6) to 26.9 (6.2), and SpO₂, increased from 90.7 (3.5) to 92.7 (3.2) with a decrease of oxygen flow rate from 27.4 (13.3) to 23.3 (10.7).
Nightingale et al.[85], 2020	32624495	Retrospective study	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 122 [97–175]	CPAP n = 24 Interface: face mask PEEP 8.75 [7.5–10] cmH₂O	CPAP failure 42% [95% CI 24 to 61]	21% [9 to 40]	Over half of patients (58%) avoided mechanical ventilation and a total of 19 out of 24 (79%) were discharged	There have been no cases of COVID-19 among nursing staff who looked after this cohort of patients.
Noeman-Ahmed et al.[86], 2020	33140491	Retrospective study	Acute Respiratory Care Unit	COVID-19 AHRF PaO₂/FiO₂ 123.15 (59.56) Patients with no limitations of treatment n = 41 Patients with limitations of treatment n = 11	CPAP n = 52 Interface: full-face mask Starting PEEP 10 cmH₂O titrated to 12.5 cmH₂O or 15 cmH₂O if SpO₂ is ≤ 94% with a FiO2 of 60%.	Patients with no limitations of treatment CPAP failure 51% [95% CI 36 to 66]	Patients with no limitations of treatment 20% [95%CI 10 to 34] 20% Patients with limitations of treatment 91% [95% CI 62 to 98]	CPAP success rate in the overall cohort was 40% with a mortality of 23%.	Predictors of success were: SpO2/FiO2, PaO₂/FiO₂, respiratory rate, neutrophil to lymphocyte ratio.
Oranger et al.[86], 2020	32430410	Retrospective study with short term historical control	Non-ICU	COVID-19 AHRF O₂ > 6 l/min to maintain SpO₂ ≥ 92%	case CPAP n = 38 control SOT n = 14 Interface: face mask with high end domiciliary ventilator PEEP 10 (adjusted between 8 and 12) cmH₂O CPAP was delivered for 8 [4–11] hours per day	Day 7 follow-up control SOT failure 54% [95% CI 33 to 79] case CPAP 24% [95% CI 13 to 39]	Day 7 follow-up control SOT 21% [95% CI 8 to 48] case CPAP 0 [95% CI 0 to 9%]	CPAP is feasible in deteriorating COVID-19 patients managed in a pulmonology unit.	None of the CPAP patients had to be intubated under cardiac arrest or high emergency conditions.
Pagano et al.[91], 2020	32629100	Observational prospective study	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 152 (82)	CPAP n = 18 Interface: Helmet PEEP 10 cmH₂O FiO₂ titrated to SpO₂ > 93%.	CPAP ETI rate 22% [95% CI 9 to 45] The number of patients with no limitations of treatment and patients with limitations of treatment is not clearly defined.	Overall mortality 61% [95% CI 39 to 80]	Eleven patients died (61%), 4 among the responders (defined as patients with an improve of PaO₂/FiO₂ of at least 15% after 1 h of CPAP) and 7 in nonresponders	Among responders 5 (27.7%) patients showed improvement in lung ultrasound score.
Vaschetto et al.[74^▪], 2021	33527074	Retrospective multicenter study	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 108 [71–157] Patients with no limitations of treatment n = 397 Patients with limitations of treatment n = 140	CPAP n = 537 Interface: Helmet n = 399 (74%) Face mask n = 123 (23%) Both n = 15 (3%) PEEP 10 [10–12] cmH₂O	Patients with no limitations of treatment 45% [95% CI 41 to 50]	Overall mortality 34% [95% CI 30 to 38] Patients with no limitations of treatment group mortality 21% [95% CI 17 to 25] Limitations of treatment mortality 73% [95% CI 65 to 79]	CPAP is feasible outside the ICU, with overall in-hospital mortality similar to that reported in other studies. Mortality is closely related to the therapeutic goal, patients having limitations of treatment being affected by much higher mortality.	Intubation delay represents a risk factor for mortality (hazard ratio 1.093, 95% CI 1.010–1.184).

Values are displayed as means (SD) or medians [Interquartile range].

Failure was defined as either intubation, death while still on noninvasive respiratory support, or escalation to other noninvasive respiratory support to avoid endotracheal intubation. AHRF, acute hypoxemic respiratory failure; ARDS, acute respiratory distress syndrome; awake PP, awake prone position; CPAP, continuous positive end-expiratory pressure; FiO₂, fraction of inspired oxygen; HFNO, high-flow nasal oxygen; ICU, intensive care unit; IQR, interquartile range; NIV, noninvasive ventilation; PaO₂, partial pressure of arterial oxygen; PEEP, positive end-expiratory pressure; SAPS, Simplified Acute Physiology Score; SOFA Sequential Organ Failure Assessment; SpO₂, peripheral capillary oxygen saturation; VFD, Ventilatory Free Days.